Engagement of the multicomponent antigen receptor in T cells (TCR) results in rapid activation of a protein tyrosine kinase pathway. To fully understand the function of this pathway, the kinase and its substrates must be characterized. We have previously shown that the protein tyrosine kinase p60-fyn is associated with the TCR. Current studies demonstrate specific sites within the kinase molecule responsible for this interaction. Another candidate for a TCR-protein tyrosine kinase is ZAP, a protein that binds to the activated TCR. Recent work from our laboratory demonstrates that tandem SH2 domains in this kinase are responsible for its interaction with TCR subunits following their tyrosine phosphorylation. One substrate for tyrosine kinases activated by the TCR is the 100kD valosin-containing protein (VCP). As a first step in understanding the effect of tyrosine phosphorylation on this protein, sites of phosphorylation have been mapped to the C-terminus of VCP. The protein has also been shown to have ATPase activity, as predicted from sequence analysis. Tyrosine phosphorylation of VCP has no effect on ATPase activity. Abnormal tyrosine phosphorylation of substrates has been detected in T cells that are infected with human immunodeficiency virus (HIV). One of the prominent substrates in this system is the protein kinase, p34cdc2, a regulator of mitosis. Accumulation of tyrosine phosphate on this enzyme correlates with the cell cycle arrest at G2/M that can be observed with HIV infection.